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Fu R, Ling D, Zhang Q, Jiang A, Pang H. Harnessing Nur77's mitochondrial apoptotic pathway: A promising therapeutic strategy for targeted disease intervention. Biomed Pharmacother 2025; 187:118091. [PMID: 40286599 DOI: 10.1016/j.biopha.2025.118091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025] Open
Abstract
The role of mitochondria in disease development cannot be overlooked, and the targeting of mitochondria for the treatment of disease has emerged as a significant area of research in recent years. Mitochondria are the control center of the intrinsic apoptotic pathway, and their normal functions are finely regulated by a series of complex mechanisms. The nuclear receptor Nur77 is closely related to the functions of the mitochondria and is an active pro-apoptotic member of the nuclear receptor superfamily. The translocation of Nur77 to the mitochondria can promote the conversion of the anti-apoptotic protein Bcl-2 to a pro-apoptotic state, disrupt the balance between mitochondrial fission and fusion, and inhibit mitophagy. These effects lead to irreversible damage to mitochondria and apoptosis, ultimately accelerating the progression of the disease. Here, we review the mechanism and targeted drug development of the mitochondrial apoptosis pathway activated by Nur77 in human diseases, helping to understand the new advances in disease treatment.
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Affiliation(s)
- Ruihai Fu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, PR China
| | - Dandan Ling
- Clinical Research Center for Placental Medicine In Hunan Province, Changsha City, Hunan Province, PR China; Department of Obstetrics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha City, Hunan Province, PR China
| | - Qiqi Zhang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, PR China
| | - Aifang Jiang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, PR China; School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, PR China
| | - Haiyan Pang
- Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong Province, PR China; School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, PR China.
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Chen J, Zhao T, Hong W, Li H, Ao M, Zhong Y, Chen X, Qiu Y, Wang X, Wu Z, Lin T, Li B, Chen X, Fang M. Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy. Acta Pharm Sin B 2024; 14:5493-5504. [PMID: 39807329 PMCID: PMC11725030 DOI: 10.1016/j.apsb.2024.07.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/03/2024] [Accepted: 07/04/2024] [Indexed: 01/16/2025] Open
Abstract
The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.
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Affiliation(s)
- Jun Chen
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Taige Zhao
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Wenbin Hong
- Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
| | - Hongsheng Li
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Mingtao Ao
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
- School of Pharmacy, Hubei University of Science and Technology, Xianning 437100, China
| | - Yijing Zhong
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Xiaoya Chen
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Yingkun Qiu
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Xiumin Wang
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Zhen Wu
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
| | - Tianwei Lin
- School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Baicun Li
- Center of Respiratory Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, State Key Laboratory of Respiratory Health and Multimorbidity, Beijing 100029, China
| | - Xueqin Chen
- Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
| | - Meijuan Fang
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China
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Chaisupasakul P, Pekthong D, Wangteeraprasert A, Kaewkong W, Somran J, Kaewpaeng N, Parhira S, Srisawang P. Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells. PLoS One 2024; 19:e0300051. [PMID: 38527038 PMCID: PMC10962855 DOI: 10.1371/journal.pone.0300051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 02/15/2024] [Indexed: 03/27/2024] Open
Abstract
The cytotoxicity of the ethyl acetate fraction of the Calotropis gigantea (L.) Dryand. (C. gigantea) stem bark extract (CGEtOAc) has been demonstrated in many types of cancers. This study examined the improved cancer therapeutic activity of sorafenib when combined with CGEtOAc in HepG2 cells. The cell viability and cell migration assays were applied in HepG2 cells treated with varying concentrations of CGEtOAc, sorafenib, and their combination. Flow cytometry was used to determine apoptosis, which corresponded with a decline in mitochondrial membrane potential and activation of DNA fragmentation. Reactive oxygen species (ROS) levels were assessed in combination with the expression of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway, which was suggested for association with ROS-induced apoptosis. Combining CGEtOAc at 400 μg/mL with sorafenib at 4 μM, which were their respective half-IC50 concentrations, significantly inhibited HepG2 viability upon 24 h of exposure in comparison with the vehicle and each single treatment. Consequently, CGEtOAc when combined with sorafenib significantly diminished HepG2 migration and induced apoptosis through a mitochondrial-correlation mechanism. ROS production was speculated to be the primary mechanism of stimulating apoptosis in HepG2 cells after exposure to a combination of CGEtOAc and sorafenib, in association with PI3K/Akt/mTOR pathway suppression. Our results present valuable knowledge to support the development of anticancer regimens derived from the CGEtOAc with the chemotherapeutic agent sorafenib, both of which were administered at half-IC50, which may minimize the toxic implications of cancer treatments while improving the therapeutic effectiveness toward future medical applications.
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Affiliation(s)
- Pattaraporn Chaisupasakul
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand
| | - Dumrongsak Pekthong
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
- Center of Excellence for Environmental Health and Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
| | | | - Worasak Kaewkong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Julintorn Somran
- Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok, Thailand
| | - Naphat Kaewpaeng
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand
- Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
| | - Supawadee Parhira
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand
- Center of Excellence for Environmental Health and Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
| | - Piyarat Srisawang
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand
- Center of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
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Zhou M, Boulos JC, Klauck SM, Efferth T. The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells. Cell Biol Toxicol 2023; 39:2971-2997. [PMID: 37322258 PMCID: PMC10693532 DOI: 10.1007/s10565-023-09813-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 05/23/2023] [Indexed: 06/17/2023]
Abstract
Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.
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Affiliation(s)
- Min Zhou
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128, Mainz, Germany
| | - Joelle C Boulos
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128, Mainz, Germany
| | - Sabine M Klauck
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Disease (NCT), 69120, Heidelberg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
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5
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Ainembabazi D, Zhang Y, Turchi JJ. The mechanistic role of cardiac glycosides in DNA damage response and repair signaling. Cell Mol Life Sci 2023; 80:250. [PMID: 37584722 PMCID: PMC10432338 DOI: 10.1007/s00018-023-04910-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/17/2023]
Abstract
Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.
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Affiliation(s)
- Diana Ainembabazi
- Department of Medicine, School of Medicine, Joseph E Walther Hall, Indiana University, 980 W. Walnut St, C560, R3-C560, Indianapolis, IN 46202 USA
| | - Youwei Zhang
- Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA
| | - John J. Turchi
- Department of Medicine, School of Medicine, Joseph E Walther Hall, Indiana University, 980 W. Walnut St, C560, R3-C560, Indianapolis, IN 46202 USA
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Nur77 Serves as a Potential Prognostic Biomarker That Correlates with Immune Infiltration and May Act as a Good Target for Prostate adenocarcinoma. Molecules 2023; 28:molecules28031238. [PMID: 36770929 PMCID: PMC9921667 DOI: 10.3390/molecules28031238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/06/2023] [Accepted: 01/17/2023] [Indexed: 01/31/2023] Open
Abstract
Prostate adenocarcinoma (PRAD) is the most frequent malignancy, and is the second leading cause of death due to cancer in men. Thus, new prognostic biomarkers and drug targets for PRAD are urgently needed. As we know, nuclear receptor Nur77 is important in cancer development and changes in the tumor microenvironment; whereas, the function of Nur77 in PRAD remains to be elucidated. The TCGA database was used to explore the Nur77 expression and its role in the prognosis of PRAD. It was shown that Nur77 was down regulated in PRAD, and low Nur77 expression was correlated with advanced clinical pathologic characteristics (high grade, histological type, age) and poor prognosis. Furthermore, key genes screening was examined by univariate Cox analysis and Kaplan-Meier survival. Additionally, Nur77 was closely related to immune infiltration and some anti-tumor immune functions. The differentially expressed genes (DEGs) were presented by protein-protein interaction (PPI) network analysis. Therefore, the expression level of Nur77 might help predict the survival of PRAD cases, which presents a new insight and a new target for the treatment of PRAD. In vitro experiments verified that natural product malayoside targeting Nur77 exhibited significant therapeutic effects on PRAD and largely induced cell apoptosis by up-regulating the expression of Nur77 and its mitochondrial localization. Taken together, Nur77 is a prognostic biomarker for patients with PRAD, which may refresh the profound understanding of PRAD individualized treatment.
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Niu T, Wei Z, Fu J, Chen S, Wang R, Wang Y, Zheng R. Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway. Front Pharmacol 2023; 13:1080412. [PMID: 36686679 PMCID: PMC9846499 DOI: 10.3389/fphar.2022.1080412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/21/2022] [Indexed: 01/05/2023] Open
Abstract
Introduction: Venlafaxine is one of the most commonly used anti-depressant and antineoplastic drug. Previous studies have predicted venlafaxine as an anti-cancer compound, but the therapeutic effects of venlafaxine in melanoma have not yet been demonstrated. Nur77 is an orphan nuclear receptor that highly expressed in melanoma cells and can interact with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic protein. Method: We examined the effects of venlafaxine in MV3 cells in vitro and MV3 xenograft tumor in nude mice. Western-blot, PCR, TUNEL assay and immunofluorescence were used to reveal the growth of melanoma cells. Results: Here, our data revealed that venlafaxine could reduce the growth, and induce apoptosis of melanoma cells through a Nur77-dependent way. Our results also showed that treatment with venlafaxine (20 mg/kg, i.p.) potently inhibited the growth of melanoma cells in nude mice. Mechanistically, venlafaxine activated JNK1/2 signaling, induced Nur77 expressions and mitochondrial localization, thereby promoting apoptosis of melanoma cells. Knockdown of Nur77 and JNK1/2, or inhibition of JNK1/2 signaling with its inhibitor SP600125 attenuated the anti-cancer effects of venlafaxine. Conclusion: In summary, our results suggested venlafaxine as a potential therapy for melanoma.
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Affiliation(s)
- Ting Niu
- Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Zhiying Wei
- Department of Pharmacy, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jiao Fu
- Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shu Chen
- Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ru Wang
- Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yuya Wang
- Department of Pharmacy, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ruihe Zheng
- Department of Pharmacy, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
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Meneses-Sagrero SE, Rascón-Valenzuela LA, García-Ramos JC, Vilegas W, Arvizu-Flores AA, Sotelo-Mundo RR, Robles-Zepeda RE. Calotropin and corotoxigenin 3-O-glucopyranoside from the desert milkweed Asclepias subulata inhibit the Na +/K +-ATPase activity. PeerJ 2022; 10:e13524. [PMID: 35673388 PMCID: PMC9167584 DOI: 10.7717/peerj.13524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/10/2022] [Indexed: 01/17/2023] Open
Abstract
Na+/K+-ATPase is an essential transmembrane enzyme found in all mammalian cells with critical functions for cell ion homeostasis. The inhibition of this enzyme by several cardiotonic steroids (CTS) has been associated with the cytotoxic effect on cancer cell lines of phytochemicals such as ouabain and digitoxin. This study evaluated the inhibitory capacity of cardenolides calotropin and corotoxigenin 3-O-glucopyranoside (C3OG) from Asclepias subulata over the Na+/K+-ATPase activity in vitro and silico. The inhibitory assays showed that calotropin and C3OG decreased the Na+/K+-ATPase activity with IC50 values of 0.27 and 0.87 μM, respectively. Furthermore, the molecules presented an uncompetitive inhibition on Na+/K+-ATPase activity, with Ki values of 0.2 μM to calotropin and 0.5 μM to C3OG. Furthermore, the molecular modeling indicated that calotropin and C3OG might interact with the Thr797 and Gln111 residues, considered essential to the interaction with the Na+/K+-ATPase. Besides, these cardenolides can interact with amino acid residues such as Phe783, Leu125, and Ala323, to establish hydrophobic interactions on the binding site. Considering the results, these provide novel evidence about the mechanism of action of cardenolides from A. subulata, proposing that C3OG is a novel cardenolide that deserves further consideration for in vitro cellular antiproliferative assays and in vivo studies as an anticancer molecule.
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Affiliation(s)
| | | | - Juan C. García-Ramos
- Escuela de Ciencias de la Salud, Universidad Autónoma de Baja California, Ensenada, Baja California, México
| | - Wagner Vilegas
- Instituto de Biociências, São Paulo State University, Sao Paulo, Brasil
| | | | - Rogerio R. Sotelo-Mundo
- Laboratorio de Estructura Molecular, Centro de Investigación en Alimentación y Desarrollo AC, Hermosillo, Sonora, México
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Ye T, Chen R, Zhou Y, Zhang J, Zhang Z, Wei H, Xu Y, Wang Y, Zhang Y. Salvianolic acid A (Sal A) suppresses malignant progression of glioma and enhances temozolomide (TMZ) sensitivity via repressing transgelin-2 (TAGLN2) mediated phosphatidylinositol-3-kinase (PI3K) / protein kinase B (Akt) pathway. Bioengineered 2022; 13:11646-11655. [PMID: 35505656 PMCID: PMC9276020 DOI: 10.1080/21655979.2022.2070963] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Glioma originated from excessively proliferative and highly invaded glial cells is a common intracranial malignant tumor with poor prognosis. Resistance to temozolomide (TMZ) is a clinical challenge in glioma treatment due to the fact that chemoresistance remains a main obstacle in the improvement of drug efficacy. Salvianolic acid A (Sal A), originated from traditional Chinese herbal medicine Salvia miltiorrhiza, possesses anti-tumor effects and could facilitate the delivery of drugs to brain tumor tissues. In the present work, effects of Sal A on the viability, proliferation, migration, invasion and apoptosis of human glioma cell line U87 cells as well as influence of Sal A on TMZ resistance were measured, so as to identify the biological function of Sal A in the malignant behaviors and chemoresistance of glioma cells. Additionally, activation of TAGLN2/PI3K/Akt pathway in glioma cells was also detected to investigate whether Sal A could regulate TAGLN2/PI3K/Akt to manipulate the progression of glioma and TMZ resistance. Results discovered that Sal A treatment reduced the viability, repressed the proliferation, migration and invasion of glioma cells as well as promoted the apoptosis of glioma cells. Besides, Sal A treatment suppressed TAGLN2/PI3K/Akt pathway in glioma cells. Sal A treatment strengthened the suppressing effect of TMZ on glioma cell proliferation and reinforced the promoting effect of TMZ on glioma cell apoptosis, which were abolished by upregulation of TAGLN2. To conclude, Sal A treatment could suppress the malignant behaviors of glioma cells and improve TMZ sensitivity through inactivating TAGLN2/PI3K/Akt pathway.
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Affiliation(s)
- Tingting Ye
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Rongrong Chen
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Yu Zhou
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Juan Zhang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Zhongqin Zhang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Hui Wei
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Yan Xu
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Yulan Wang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
| | - Yinlan Zhang
- Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China
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10
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Li X, Cao X, Zhao H, Guo M, Fang X, Li K, Qin L, He Y, Liu X. Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis. Front Cell Dev Biol 2022; 9:780121. [PMID: 34988077 PMCID: PMC8721100 DOI: 10.3389/fcell.2021.780121] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.
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Affiliation(s)
- Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Xiaopei Cao
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hanqiu Zhao
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Xiaoyu Fang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Ke Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Lu Qin
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Yuanzhou He
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China
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11
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Xia M, Cao H, Zheng J, Yao Y, Xu F, Lu G, Ma Y, Zhou J. A novel stilbene derivative (GMQ3) suppressed proliferation and induced apoptosis in lung cancer via the p38-MAPK/SIRT1 pathway. Biochem Pharmacol 2021; 193:114808. [PMID: 34678220 DOI: 10.1016/j.bcp.2021.114808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Lung cancer is the primary cause of cancer-related mortality worldwide. The anticancer effect of stilbene has been noted in various tumor types. GMQ3, which has a stilbene-mimicking skeleton, is a novel small-molecule compound with promising antitumor activity. Our results revealed that GMQ3 not only suppressed cell proliferation and cell migration of lung cancer cells but also led to G1 phase cell cycle arrest and triggered caspase-dependent apoptosis. Furthermore, investigation of the molecular mechanism showed that GMQ3 could inhibited proliferation and induced apoptosis via the p38-MAPK/SIRT1 pathway both in vitro and in vivo. Xenograft tumor mouse models showed that GMQ3 significantly inhibited tumor growth in vivo without affecting body weight. Our findings indicated that GMQ3 exerts a strong anticancer action by suppressing cell proliferation, inhibiting cell migration and inducing cell apoptosis. Moreover, the efficacy of GMQ3 was enhanced in the presence of CDK4/6 inhibitor Abemaciclib. We conclude that GMQ3 is a promising agent with potential for lung cancer.
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Affiliation(s)
- Mengling Xia
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - He Cao
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Zheng
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yinan Yao
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fei Xu
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guohua Lu
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yongmin Ma
- Institute of Advanced Studies and School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou, China.
| | - Jianying Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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12
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Li S, Gao J, Hou L, Gao Y, Sun J, Zhang N, Fan B, Wang F. The Small Molecule Fractions of Floccularia luteovirens Induce Apoptosis of NSCLC Cells through Activating Caspase-3 Activity. Int J Mol Sci 2021; 22:ijms221910609. [PMID: 34638946 PMCID: PMC8508712 DOI: 10.3390/ijms221910609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/25/2021] [Accepted: 09/27/2021] [Indexed: 01/18/2023] Open
Abstract
Floccularia luteovirens is a rare wild edible and medicinal fungus endemic to the Qinghai-Tibet Plateau. In this study, the hollow fiber membranes with molecular weights of 50 kDa, 6 kDa and 3 kDa were used to extract different fractions of F. luteovirens, which were named as #1, #2 and #3. Then the antitumor activity of these fractions on NSCLC cell lines, PC9 and NCI-H460, were investigated by using MTT assay, flow cytometry analysis and Western blot assay. The results indicated that the #2 and #3 fractions showed obviously inhibitory activities on PC9 and NCI-H460 tumor cells and proved that these small molecule fractions induced apoptosis of NSCLC cells by activating caspase-3. Finally, a total of 15 components, including six amino acids, two nucleosides, two glycosides, two terpenoids, one phenylpropanoid, one ester and one alkaloid, were identified in #2 and #3 fractions. This is the first evidence that the small molecule components of F. luteovirens were able to inhibit lung cancer by inducing apoptosis in a caspase-3 manner. The present study indicated the benefits of F. luteovirens in lung cancer treatment, which might be a potential resource of functional food and drugs.
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